The bisphosponates, which are salts of bisphosphonic acids, are an important class of medicaments useful in the treatment of bone disorders such as Paget's disease and osteoporosis. See, e.g., Robert Marcus, Agents Affecting Calcification and Bone Turnover, in Goodman and Gilman's The Pharmacological Basis of Therapeutics 1519, 1537–39 (Joel G. Hardman & Lee E. Limbird, eds. in chief, 9th ed., 1996). The sodium salt of risedronic acid (i.e. [1-hydroxy-2-(3-pyridinyl)ethylidene]bis[phosphonic acid] monosodium salt), marketed under the trade name Actonel® and the sodium salt of [4-amino-1-hydroxybutylidene]bis [phosphonic acid] are examples of pharmaceutically useful bisphosphonates.
The bisphosphonates are derived from the corresponding bisphosphonic acids. Several methods have been reported for preparing 1-hydroxy-1,1-bisphosphonic acids. The syntheses are based on reacting a carboxylic acid with a mixture of phosphorous acid and one of the following phosphorous halides: phosphorous trichloride (PCl3), phosphorous oxychloride (POCl3), phosphorous pentachloride (PCl5), phosphorous tribromide (PBr3), phosphorous oxybromide (POBr3) or phosphorous pentabromide (PBr5), then quenching the reaction mixture with water or a nonoxidizing aqueous acid, followed by heating to hydrolyze the phosphorous intermediates to the final product.
U.S. Pat. No. 4,407,761 describes a synthesis of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (alendronic acid) and other bisphosphonic acids. The reaction can be carried out in the presence of a diluent, especially chlorinated hydrocarbons, especially chlorobenzene, which does not solubilize the reaction components and serves only as a heat carrier. The reaction starts as a two-phase system, in which the melted phase gradually thickens into a non-stirrable mass. This semi-solid sticky mass finally turns into a hard, rigid material, coating the walls of the reaction vessel, fouling the reactor and preventing smooth heat transfer and complicating product work-up. This process might be suitable for laboratory preparation of gram quantities of the product however, for commercial production it is not acceptable. A solution to this caking and fouling problem is clearly required before the reaction can be economically practiced on a commercial scale.
The above-described flaws of the process of the '761 patent were acknowledged by Kieczykowski et al. See, e,g, Kieczykowski et al., J. Org. Chem, 60(25) 8310, 8311(1995). In application for Canadian Patent 2,018,477 and 2,044,923, Kieczykowski et al. revealed a solution to the solidification and fouling problem. Methanesulfonic acid (MSA) was used to solubilize the reaction components and keep the reaction mixture fluid up to completion of the reaction. Although the problems with physical characteristics of the reaction appeared solved, a safety problem surfaced.
Methanesulfonic acid reacts with phosphorous trichloride and, under adiabatic conditions, the reaction becomes self-heating at 85° C. and an uncontrolled exotherm occurs at reaction temperatures >140° C. Kieczykowski et al. acknowledged this safety issue and raised it in Example 1 of both above-cited Canadian applications. The safety concern is mentioned by the authors in somewhat more detail in the above cited article in the Journal of Organic Chemistry.
U.S. Pat. No. 5,908,959 (corresponding to WO 98/34940), assigned to Apotex Inc., describes a process for preparing alendronic acid comprising reacting 4-aminobutyric acid (GABA) with phosphorous acid and phosphorous trichloride in the presence of a polyalkylene(glycol) or derivatives thereof. However, it was reported that large quantities of polyalkylene(glycol), as well as toluene, are required for the reaction, making it inefficient for use on a large scale.
There remains a need for a safe and efficient industrial process for preparing bisphosphonic acids, especially risedronic acid, alendronic acid, and zoledronic acid that is free of the solidification problem.
The present inventors have surprisingly found that yield is improved and fouling caused by solidification problems is reduced if, in the reaction between a carboxylic acid (e.g. 3-pyridyl acetic acid or its hydrochloride), H3PO3, and, for example, POCl3, an aromatic hydrocarbon such as toluene, especially in the presence of ortho-phosphoric acid as codiluent, or a silicon oil such as polydimethylsiloxane, is used as a diluent instead of previously used halogenated hydrocarbons. The present inventors have also surprisingly found that the solidification and reactor fouling problem can be eliminated if the reaction between carboxylic acid, phosphorous acid, and, for example, POCl3, is carried out in a diluent that is an aromatic hydrocarbon (e.g. toluene) in the presence of a heterogeneous solid support.